Age-related macular degeneration (AMD) causes irreversible central visual loss in the aged population worldwide. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation creates a predisposition to the disease. In 2003, we initiated this project by recruiting advanced AMD patients and age-matched control individuals with normal retinas. To date, 477 individuals have been enrolled and 115 histopathological cases with AMD and age-matched controls have been collected. We continue to analyze parts of 835 DNA samples from the Blue Mountain Eye Study from Australia and 534 DNA samples from the AREDS project in the USA, as some DNA samples have run out. We have compared the allelic frequencies of single nucleotide polymorphisms (SNPs) within candidate genes between AMD and control subjects, followed by functional studies of these SNPs by in vitro and/or in vivo experiments. Through this approach, we have identified genetic risk factors of AMD and the possible roles of these gene variations in the pathogenesis of the disease. Based on the information obtained from the above approaches, a genetically engineered animal (Ccl2/Cx3cr1 double deficiencies on rd8 background mice, DKO rd8) was generated to act as an AMD model in 2007. While caution must always be taken in translating findings in mouse models to findings in humans, the AMD-like phenotype of DKO rd8 makes the model a useful tool for evaluating potential therapies for AMD. In FY2015, (1) we have continued to work with collaborators to use our DKO rd8 model to study disease pathogenesis and therapeutic approaches to AMD by evaluating the roles of gut commensal microbiota and Ixolaris, a tissue factor inhibitor (collaboration with Drs. Jose Ribero and Ivo Francischetti of NIAID) that were reported at ARVO 2015; (2) we published the association study between RAD51, FPR1 (collaboration with Dr. Calvin Pang of Chinese University of Hong Kong), and UBE3D (collaboration with Dr. Xiaoxin Li of Peking University) and AMD; (3) we performed in vitro studies on inflammasomes and related molecules/pathways with ARPE-19 cells, human RPE cells (collaboration with Dr. Shusheng Wang of Tulane Univeristy), and mouse retinal stem cells (collaboration with Ting Xie of Stowers Institute for Medical Research); (4) we evaluated cell death forms/pathways in RPE and photoreceptors that are the most critical cells in AMD. As of May 2015, the Immunopathology Section has closed with the retirement of the principal investigator, Dr. Chan.